Antimicrobial peptides and proteins play an important role in innate host defenses and are believed to be particularly important at mucosal surfaces that form the initial barrier between the host and the external environment. Such peptides are found in large quantities in the colonic epithelium. The peptides can be considered as endogenous antibiotics and are widespread in nature as immediate defense effectors. They are mainly stored in vacuoles of granulocytes ready for activation upon stimulation or secreted directly onto mucosal and other surfaces by epithelial cells.
A human antimicrobial peptide has been identified and is referred to as LL-37, a 37-residue peptide present in neutrophils, epithelial cells and lymphocytes. Both isolated and chemically synthesised LL-37 show antimicrobial activity in vitro.
Certain bacteria have evolved mechanisms to overcome the antimicrobial peptide barrier, such as Shigella bacteria which down-regulate LL-37 expression in the colon epithelium.
Rabbani et al. (Short-Chain Fatty Acids Improve Clinical, Pathologic, and Microbiologic Features of Experimental Shigellosis. The Journal of Infectious Diseases 1999; 179:390-7) investigated that naturally occurring short chain fatty acids (SCFAs; acetate, propionate, and butyrate in 60:30:40 ratio) which occur as fermentation products in the gut. The authors used a rabbit model of shigellosis. They reported that the mixture, given by colonic infusion into the rabbits with acute shigellosis, improved clinical, pathologic, and bacteriologic characteristics.
Hase et al. (Cell Differentiation Is a Key Determinant of Cathelicidin LL-37/Human Cationic Antimicrobial Protein 18 Expression by Human Colon Epithelium. INFECTION AND IMMUNITY, February 2002, vol 70, No 2 p. 953-963) reported that infection in vitro of HCA-7 cells with Salmonella enterica serovar Dublin or enteroinvasive Escherichia coli modestly upregulated LL-37/hCAP18 mRNA expression. The authors concluded that differentiated human colon epithelium expresses LL-37/hCAP18 as part of its repertoire of innate defense molecules.
Schauber et al. (Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut 2003; 52:735-741.) investigated the effect of naturally occurring SCFAs on LL-37 expression in vivo and in vitro. These authors report that following exposure to butyrate, isobutyrate and propionate, expression of the LL-37 mRNA increases in vitro in colonocytes. The authors are cautious about the possible consequences of increased antimicrobial peptide expression on the commensal intestinal flora, which is critical for protection of the mucosa against enteropathogenic microbes. They note a pathological increase in the activity of endogenous antibiotics would not then be beneficial to the host but might have deleterious consequences.
Raqib et al. (Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc. Natl. Acad. Sci. 2006; 103: 9178-9183.) reported that butyrate treatment of rabbits resulted in reduced clinical illness and bacterial load in the stool and significant upregulation of CAP-18 (the rabbit homologue of LL-37) in the surface epithelium.
Other molecules have also been investigated for their possible utility in stimulating natural defensins.
WO2000-09137 (Magainin Pharmaceuticals) describes newly isolated aminosterol compounds and pharmaceutical compositions based on the aminosterol compounds are described. Methods for the treatment of various disorders, for example, a microbial infection, are also described
US2002-0076393 (Fehlbaum et al.) describe the use of isoleucine or active isomers or analogs thereof for stimulating production of defensin. It should be noted that the claims refer, inter alia, to one such analog being butyrate or an active derivative thereof. However where butyrate was tested and it appeared to be less active than isoleucine at similar concentrations (see FIG. 7 therein).
US2003-0109582 (Zasloff) describe the use of isoleucine compounds for stimulating Paneth cells to release natural antimicrobial agents including peptides, to reduce or eliminate pathogenic organisms in the GI tract of mammalian bodies, including humans, utilizing an active isoleucine compound as a secretagogue. “Isoleucine compounds” are defined as including ‘isoleucine butyrate’ though this compound is not described or tested.
U.S. Pat. No. 7,311,925 (Zasloff) describes methods of blocking microbial adherence to a eukaryotic cell surface in a mammal by applying a pharmacologically acceptable composition containing at least one compound selected from the group consisting of isoleucine, an active isomer thereof, and an active analog thereof, to said surface in a microbial blocking quantity. Active analogs of isoleucine are defined as including ‘isoleucine butyrate’ though this compound is not described or tested.
US20080038374 (Stahle) describes use of a vitamin D compound, which is able to specifically and directly up-regulate hCAP18, for the manufacturing of a medicament with antimicrobial effect for treatment of conditions deficient in LL-37, such as chronical ulcers, and atopic dermatitis.
WO/2008/073174 (GALLO) describes methods and compositions for modulating gene expression and cathelicidin the innate immune response by 1,25(OH)2 vitamin D3 (1,25D3). That compound is tested alongside non-specific histone deacetylase inhibitors (HDACi) including butyrate or trichostatin A.
Hata et al. (2008) “Administration of oral vitamin D induces cathelicidin production in atopic individuals” J ALLERGY CLIN IMMUNOL, VOLUME 122, NUMBER 4, described a study in which 14 normal controls and 14 atopic subjects with moderate to severe atopic dermatitis were treated with oral vitamin D3 to see if this could overcome the relative deficiency in induction of cathelicidin in the atopic patients. After supplementation with 4000 IU/d oral vitamin D for 21 days, AD lesional skin showed a statistically significant increase in cathelicidin expression.
Despite the above disclosures, it will be appreciated that the provision of compounds or combinations of compounds for use in enhancing the innate immune response, for example in the gut, would provide a contribution to the art.